Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3–7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusio...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-11-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/9/12/164 |
| _version_ | 1797763216082731008 |
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| author | Wei Wu Franziska Haderk Trever G. Bivona |
| author_facet | Wei Wu Franziska Haderk Trever G. Bivona |
| author_sort | Wei Wu |
| collection | DOAJ |
| description | Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3–7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients. |
| first_indexed | 2024-03-12T19:38:22Z |
| format | Article |
| id | doaj.art-6c0a7abe8d5d4c4186fac9ae90779e53 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:38:22Z |
| publishDate | 2017-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6c0a7abe8d5d4c4186fac9ae90779e532023-08-02T04:00:48ZengMDPI AGCancers2072-66942017-11-0191216410.3390/cancers9120164cancers9120164Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung CancerWei Wu0Franziska Haderk1Trever G. Bivona2Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USAHelen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USAHelen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USAAnaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3–7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients.https://www.mdpi.com/2072-6694/9/12/164anaplastic lymphoma kinaseALKdimerization inhibitionneoantigensCAR-Timmunotherapy |
| spellingShingle | Wei Wu Franziska Haderk Trever G. Bivona Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer Cancers anaplastic lymphoma kinase ALK dimerization inhibition neoantigens CAR-T immunotherapy |
| title | Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer |
| title_full | Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer |
| title_fullStr | Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer |
| title_full_unstemmed | Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer |
| title_short | Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer |
| title_sort | non canonical thinking for targeting alk fusion onco proteins in lung cancer |
| topic | anaplastic lymphoma kinase ALK dimerization inhibition neoantigens CAR-T immunotherapy |
| url | https://www.mdpi.com/2072-6694/9/12/164 |
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